Overproduction of Vascular Endothelial Growth Factor Related to von Hippel-Lindau Tumor Suppressor Gene Mutations and Hypoxia-Inducible Factor-1α Expression in Renal Cell Carcinomas.

ABSTRACTPurpose: The von Hippel-Lindau (VHL) tumor suppressor gene is frequently inactivated in the common type of sporadic clear cell renal cell carcinoma (RCC) as well as RCCs associated with VHL disease. The VHL protein targets hypoxia-inducible factor-1α (HIF-1α), a transcription factor that can induce vascular endothelial growth factor (VEGF) expression, for ubiquitination and degradation. Accumulation of HIF-1α caused by mutant VHL protein in tumor cells may result in VEGF over expression, which has been used to explain the increased vascularity of RCC. However, quantitative analyses of VEGF production and its correlation with VHL mutations and HIF-1α expression in authentic tissues from patients with RCC are lacking.Materials and Methods: We analyzed VHL gene mutations by direct DNA sequencing and methylation specific polymerase chain reaction in 31 paired RCC tissue samples. HIF-1α protein expression detected by immunoblotting and immunohistochemical staining, and VEGF protein measured by enzyme-l...